Is ECHS1 p.Ala138Val (c.413C>T) pathogenic?

ECHS1 p.Ala138Val (c.413C>T) is classified Pathogenic in ECHS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-10-01). AlphaMissense: ambiguous (0.536); Absent from gnomAD v4.1; Associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.

What condition is associated with ECHS1 p.Ala138Val (c.413C>T)?

ECHS1 p.Ala138Val (c.413C>T) is associated with mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (ClinVar).

How common is ECHS1 p.Ala138Val (c.413C>T) in the general population?

ECHS1 p.Ala138Val (c.413C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ECHS1 p.Ala138Val (c.413C>T)?

AlphaMissense predicts ambiguous (score 0.536) — an in-silico prediction, not a clinical call.

ECHS1 p.Ala138Val

Q: How is Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.413C>T · rs864309656 · VCV218891

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.536 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.536	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -12.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.4 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ECHS1
Protein: p.Ala138Val
Coding: c.413C>T
MANE Select: NM_004092
dbSNP: rs864309656
Type: single nucleotide variant
Location: chr10:133369905 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 138: a UniProt-annotated variant site (in echs1d; decreases enoyl-coa hydratase activity of 70%; decreases significantly protein expression); a β-strand

Full ECHS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ECHS1 p.Ala138= Conflicting classifications of pathogenicity ★ same residue
ECHS1 p.Ala138Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ECHS1 c.414+1G>A Pathogenic/Likely pathogenic ★★ same condition
ECHS1 c.88+5G>A Pathogenic/Likely pathogenic ★★ same condition
ECHS1 p.Ala132Thr Pathogenic/Likely pathogenic ★★ same condition
ECHS1 p.Ala173Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECHS1 p.Ala238Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
ECHS1 p.Ala278Thr Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/echs1-p-ala138val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown